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Monday, 27 April 2009

Influenza A virus subtype H1N1 and the Pandemic of 1918

Influenza A virus subtype H1N1

H1N1 is a subtype of the species Influenza A virus. The "H" refers to the Hemagglutinin protein, and the "N" refers to the Neuraminidase protein. H1N1 has mutated into various strains including the Spanish Flu strain (now extinct in the wild), mild human flu strains, endemic pig strains, and various strains found in birds. A variant of H1N1 was responsible for the Spanish flu pandemic that killed some 50 million to 100 million people worldwide from 1918 to 1919. A different variant exists in pig populations.

Low pathogenic H1N1 strains still exist in the wild today, causing roughly half of all flu infections in 2006. When the 1918 virus was compared with human flu viruses in 2005, it was noticed that it had alterations in just 25 to 30 of the virus's 4,400 amino acids. These changes were enough to turn a bird virus into a version that was human-transmissible.

In April 2009, an H1N1 outbreak killed over one hundred (100) in Mexico, and was believed to have infected more than 1600 individuals worldwide as of April 27, 2009. The U.S. Centers for Disease Control warned that it was possible the outbreak could develop into a pandemic.

Spanish Flu

The 1918 flu pandemic (commonly referred to as the Spanish flu) was an influenza pandemic that spread to nearly every part of the world. It was caused by an unusually virulent and deadly Influenza A virus strain of subtype H1N1. Historical and epidemiological data are inadequate to identify the geographic origin of the virus. Most of its victims were healthy young adults, in contrast to most influenza outbreaks which predominantly affect juvenile, elderly, or otherwise weakened patients. The pandemic lasted from March 1918 to June 1920, spreading even to the Arctic and remote Pacific islands. It is estimated that anywhere from 20 to 100 million people were killed worldwide, or the approximate equivalent of one third of the population of Europe, more than double the number killed in World War I. This extraordinary toll resulted from the extremely high illness rate of up to 50% and the extreme severity of the symptoms, suspected to be caused by cytokine storms. The pandemic is estimated to have affected up to one billion people: half the world's population at the time.

Some scholars have theorized that the flu probably originated in the Far East. Scholar John Barry has proposed that Haskell County, Kansas was the location of the first outbreak of flu. The disease was first observed at Fort Riley, Kansas, United States, on March 4, 1918,and Queens, New York, on March 11, 1918. In August 1918, a more virulent strain appeared simultaneously in Brest, France, in Freetown, Sierra Leone, and in the U.S. at Boston, Massachusetts. The Allies of World War I came to call it the Spanish flu, primarily because the pandemic received greater press attention after it moved from France to Spain in November 1918. Spain was not involved in the war and had not imposed wartime censorship.

Scientists have used tissue samples from frozen victims to reproduce the virus for study. Given the strain's extreme virulence there has been controversy regarding the wisdom of such research. Among the conclusions of this research is that the virus kills via a cytokine storm (overreaction of the body's immune system) which explains its unusually severe nature and the concentrated age profile of its victims. The strong immune systems of young adults ravaged the body, whereas the weaker immune systems of children and middle-aged adults caused fewer deaths.

The global mortality rate from the 1918/1919 pandemic is not known, but is estimated at 2.5 to 5% of the human population, with 20% or more of the world population suffering from the disease to some extent. Influenza may have killed as many as 25 million in its first 25 weeks (in contrast, AIDS killed 25 million in its first 25 years).Older estimates say it killed 40–50 million people while current estimates say 50 million to 100 million people worldwide were killed. This pandemic has been described as "the greatest medical holocaust in history" and may have killed more people than the Black Death.

An estimated 17 million died in India, about 5% of India's population at the time.In the Indian Army, almost 22% of troops who caught the disease died of it. In the U.S., about 28% of the population suffered, and 500,000 to 675,000 died.In Britain as many as 250,000 died; in France more than 400,000. In Canada approximately 50,000 died. Entire villages perished in Alaska and southern Africa. Ras Tafari (the future Haile Selassie) was one of the first Ethiopians who contracted influenza but survived, although many of his subjects did not; estimates for the fatalities in the capital city, Addis Ababa, range from 5,000 to 10,000, with some experts opining that the number was even higher, while in British Somaliland one official there estimated that 7% of the native population died from influenza. In Australia an estimated 12,000 people died and in the Fiji Islands, 14% of the population died during only two weeks, and in Western Samoa 22%.

This huge death toll was caused by an extremely high infection rate of up to 50% and the extreme severity of the symptoms, suspected to be caused by cytokine storms. Indeed, symptoms in 1918 were so unusual that initially influenza was misdiagnosed as dengue, cholera, or typhoid. One observer wrote, "One of the most striking of the complications was hemorrhage from mucous membranes, especially from the nose, stomach, and intestine. Bleeding from the ears and petechial hemorrhages in the skin also occurred." The majority of deaths were from bacterial pneumonia, a secondary infection caused by influenza, but the virus also killed people directly, causing massive hemorrhages and edema in the lung.

The unusually severe disease killed between 2 and 20% of those infected, as opposed to the more usual flu epidemic mortality rate of 0.1%. Another unusual feature of this pandemic was that it mostly killed young adults, with 99% of pandemic influenza deaths occurring in people under 65, and more than half in young adults 20 to 40 years old. This is unusual since influenza is normally most deadly to the very young (under age 2) and the very old (over age 70), and may have been due to partial protection caused by exposure to a previous Russian flu pandemic of 1889.

Spanish flu research

Spanish flu research concerns scientific research regarding the causes and characteristics of the "Spanish flu", a variety of influenza that in 1918 was responsible the worst influenza pandemic in modern history. Many theories about the origins and progress of the Spanish flu persisted in literature, but it wasn't until 2005, when various samples recovered from American World War I soldiers and an Inuit woman buried in the Alaskan tundra, that significant research has been possible.

Origin of Virus

One theory is that the virus strain originated at Fort Riley, Kansas, by two genetic mechanisms — genetic drift and antigenic shift — in viruses in poultry and swine which the fort bred for local consumption. Though initial data from a recent reconstruction of the virus suggested that it jumped directly from birds to humans, without traveling through swine, this has since been cast into doubt. One researcher argues that the disease was found in Haskell County, Kansas as early as January 1918.A similar and even more deadly virus had been seen earlier at British camps in France and at Aldershot.

Discovery of viral genomes

In February 1998, Johan Hultin recovered samples of the 1918 influenza from the frozen corpse of a Native Alaskan woman buried for nearly eight decades in permafrost near Brevig Mission, Alaska. He brought the samples to a team led by Jeffery Taubenberger of the US Armed Forces Institute of Pathology (AFIP). Brevig Mission lost approximately 85% of its population to the 1918 flu in November 1918. One of the four recovered samples contained viable genetic material of the virus. This sample provided scientists a first-hand opportunity to study the virus, which was inactivated with guanidinium thiocyanate before transport. This sample and others found in AFIP archives allowed researchers to completely analyze the critical gene structures of the 1918 virus. "We have now identified three cases: the Brevig Mission case and two archival cases that represent the only known sources of genetic material of the 1918 influenza virus", said Taubenberger, chief of AFIP's molecular pathology division and principal investigator on the project.

The February 6, 2004 edition of Science magazine reported that two research teams, one led by Sir John Skehel, director of the National Institute for Medical Research in London, another by Professor Ian Wilson of The Scripps Research Institute in San Diego, had managed to synthesize the hemagglutinin protein responsible for the 1918 flu outbreak of 1918. They did this by piecing together DNA from a lung sample from an Inuit woman buried in the Alaskan tundra and a number of preserved samples from American soldiers of the First World War. The teams had analyzed the structure of the gene and discovered how subtle alterations to the shape of a protein molecule had allowed it to move from birds to humans with such devastating effects.

On October 5, 2005, researchers at the Mount Sinai School of Medicine in New York announced that the genetic sequence of the 1918 flu strain, a subtype of avian strain H1N1, had been reconstructed using historic tissue samples.

Characteristics of virus

Influenza viruses have a relatively high mutation rate that is characteristic of RNA viruses. The H5N1 virus has mutated into a variety of types with differing pathogenic profiles; some pathogenic to one species but not others, some pathogenic to multiple species.The ability of various influenza strains to show species-selectivity is largely due to variation in the hemagglutinin genes. Genetic mutations in the hemagglutinin gene that cause single amino acid substitutions can significantly alter the ability of viral hemagglutinin proteins to bind to receptors on the surface of host cells. Such mutations in avian H5N1 viruses can change virus strains from being inefficient at infecting human cells to being as efficient in causing human infections as more common human influenza virus types. This doesn't mean one amino acid substitution can cause a pandemic but it does mean one amino acid substitution can cause an avian flu virus that is not pathogenic in humans to become pathogenic in humans.

In July 2004, researchers led by H. Deng of the Harbin Veterinary Research Institute, Harbin, China and Robert Webster of the St Jude Children's Research Hospital, Memphis, Tennessee, reported results of experiments in which mice had been exposed to 21 isolates of confirmed H5N1 strains obtained from ducks in China between 1999 and 2002. They found "a clear temporal pattern of progressively increasing pathogenicity". Results reported by Webster in July 2005 reveal further progression toward pathogenicity in mice and longer virus shedding by ducks.

In December, 2008, research by Yoshihiro Kawaoka of University of Wisconsin linked the presence of the three specific genes (termed PA, PB1, and PB2) and a nucleoprotein derived from the 1918 flu samples was enough to trigger similar symptoms in animal testing.

Research of viral pathogenesis

Recent research of Taubenberger et al has suggested that the 1918 virus, like H5N1, could have arisen directly from an avian influenza virus. However, researchers at University of Virginia and Australian National University have suggested that there may be an alternative interpretation of the data used in the Taubenberger et al. paper.Taubenberger et al responded to these letters and defended their original interpretation.

Other research by Tumpey and colleagues who reconstructed the H1N1 virus of 1918 came to the conclusion that it is was most notably the polymerase genes and the HA and NA genes that caused the extreme virulence of this virus. The sequences of the polymerase proteins (PA, PB1, and PB2) of the 1918 virus and subsequent human viruses differ by only 10 amino acids from the avian influenza viruses. Viruses with seven of the ten amino acids in the human influenza locations have already been identified in currently circulating H5N1. This has led some researchers to suggest that other mutations may surface and make the H5N1 virus capable of human-to-human transmission. Another important factor is the change of the HA protein to a binding preference for alpha 2,6 sialic acid (the major form in the human respiratory tract). In avian virus the HA protein preferentially binds to alpha 2,3 sialic acid, which is the major form in the avian enteric tract. It has been shown that only a single amino acid change can result in the change of this binding preference. Altogether, only a handful of mutations may need to take place in order for H5N1 avian flu to become a pandemic virus like the one of 1918. However it is important to note that likelihood of mutation does not indicate the likelihood for the evolution of such a strain; since some of the necessary mutations may be constrained by stabilizing selection.

On 18 January 2007, Kobasa et al reported that infected monkeys (Macaca fascicularis) exhibited classic symptoms of the 1918 pandemic and died from a cytokine storm.

Blood plasma as an effective treatment

In the event of another pandemic, US military researchers have proposed reusing a treatment from the deadly pandemic of 1918 in order to blunt the effects of the flu. Some military doctors injected severely afflicted patients with blood or blood plasma from people who had recovered from the flu. Data collected during that time indicates that the blood-injection treatment reduced mortality rates by as much as 50 percent. Navy researchers have launched a test to see if the 1918 treatment will work against deadly Asian bird flu. Results thus far have been inconclusive. Human H5N1 plasma may be an effective, timely, and widely available treatment for the next flu pandemic. A new international study using modern data collection methods, would be a difficult, slow process. But many flu experts, citing the months-long wait for a vaccine for the next pandemic, are of the opinion that the 1918 method is something to consider.

In the world wide 1918 flu pandemic, "physicians tried everything they knew, everything they had ever heard of, from the ancient art of bleeding patients, to administering oxygen, to developing new vaccines and sera (chiefly against what we now call Hemophilus influenzae—a name derived from the fact that it was originally considered the etiological agent—and several types of pneumococci). Only one therapeutic measure, transfusing blood from recovered patients to new victims, showed any hint of success."

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